Nonmyeloablative Allografts in DLA-haploidentical Dogs: Engraftment and GVHD

DLA 单倍体狗的非清髓性同种异体移植：移植和 GVHD

• 批准号: 7478449
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 41.46万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478449
• 关键词: Allogenic; Allografting; Antibodies; Antigens; Autologous; Biological; Bismuth; Blood Cells; Breeding; CD45 Antigens; Canis familiaris; Cell Adhesion Molecules; Cell Transplantation; Cells; Chimeric Proteins; Chimerism; Clinical; Clinical Trials; Condition; Cyclosporine/Mycophenolate Mofetil; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Dose; Drug resistance; Engraftment; Genes; Goals; Grant; Granulocyte Colony-Stimulating Factor; HLA Antigens; Hematopoietic; High Dose Chemotherapy; Host vs Graft Reaction; Human; Immunoglobulins; Immunologics; Immunosuppressive Agents; Label; Leukocytes; Lymphocyte; Marrow; Mediating; Methotrexate; Monoclonal Antibodies; Natural Killer Cells; Patients; Pre-Clinical Model; Prevention; Principal Investigator; Radioisotopes; Range; Rate; Recovery; Residual state; Sirolimus; Stem cells; T-Lymphocyte; TNFSF5 gene; Tin; Toxic effect; Translating; Translations; Transplantation; Treatment Protocols; Work; cellular transduction; chemotherapy; graft vs host disease; graft vs host reaction; killer T cell; mycophenolate mofetil; programs; response; temozolomide

The long-term objective of this project is to develop a safe and reliable nonmyeloablative approach at hematopoietic cell transplantation (HCT) from dog leukocyte antigen (DLA)-haploidentical donors, which can be translated into clinical trials. The studies will focus on the bi-directional immunologic barriers, host-versus-graft (HVG) and graft-versus-host (GVH) reactions, which must be overcome in order to achieve both uniform and sustained hematopoietic engraftment and graft-host tolerance. Two goals were pursued during the current grant period. One included extension of work in DLA-identical littermates in which we successfully substituted monoclonal antibodies (MAbs) directed at either TCRalpha-beta or the ubiquitous hematopoietic antigen, CD45, which were labeled with an alpha-emitting radionuclide Bismuth-213 (213Bi), for 2 Gy TBI. We also established successful DLA-haploidentical grafts when recipients were treated first with an anti-CD44 antibody combined with 4.5 Gy TBI and then given mycophenolate mofetil (MMF) and cyclosporine (CSP) after HCT for control of residual HVG reactions and for GVHD prevention. However, when the TBI dose was decreased to the sublethal range of 2 Gy, the engraftment rate declined to 50%, while the remainder of the dogs eventually rejected their grafts and survived with autologous marrow recovery. Also, GVHD control, which is largely T-cell mediated, has not been uniform. The current proposal seeks to continue the studies on DLA-haploidentical grafts since development of safe approaches will expand the choice of potential donors. Two principal experimental approaches will be taken. One involves combining low-dose TBI with relatively non-toxic biological and pharmacological immunosuppressive agents, including 213Bi-labeled antibodies to natural killer (NK) cells, all aimed at reducing both host NK and T cell responses and T cell responsiveness of the graft. The other is to administer chemotherapy early after transplant to not only control GVHD but also facilitate engraftment. After we have determined the optimal tinning and dosing of posttransplantation chemotherapy, we will evaluate the use of donor cells transduced with drug resistance genes which will allow using higher doses of posttransplantation chemotherapy for both induction of donor chimerism and control of GVHD. GVHD prevention will also include control of donor lymphocyte replication with certain immunosuppressive agents, e.g., MMF and sirolimus, combined with blockers of T-cell costimulation. Our ultimate aim is to develop allogeneic HCT strategies for patients with alternative donors with the least short- and long-term toxicities, which can be successfully applied to human patients.

该项目的长期目标是开发一种安全可靠的非清髓方法 来自狗白细胞抗原（DLA）单倍体捐献者的造血细胞移植（HCT），可以 转化为临床试验。研究将重点关注双向免疫屏障、宿主抗移植物 （HVG）和移植物抗宿主（GVH）反应，必须克服这些反应才能实现这两种反应 均匀且持续的造血移植和移植物宿主耐受性。期间追求了两个目标 当前的资助期限。其中一项包括延长 DLA 相同同窝仔鼠的工作范围，其中我们 成功替代针对 TCRα-β 或普遍存在的单克隆抗体 (MAb) 造血抗原 CD45，用 α 发射放射性核素 Bismuth-213 (213Bi) 标记，用于 2 戈瑞 TBI。当受者首先接受以下治疗时，我们还成功建立了 DLA 单倍体移植物 抗 CD44 抗体与 4.5 Gy TBI 结合，然后给予吗替麦考酚酯 (MMF) 和 HCT 后使用环孢素 (CSP)，用于控制残余 HVG 反应和预防 GVHD。然而， 当TBI剂量降低至2 Gy的亚致死范围时，植入率下降至50%， 而其余的狗最终拒绝了移植物并通过自体骨髓存活下来 恢复。此外，主要由 T 细胞介导的 GVHD 控制也并不统一。 目前的提案旨在继续对 DLA-半相合移植物的研究，因为 安全的方法将扩大潜在捐助者的选择。两种主要的实验方法将是 采取。其中之一涉及将低剂量 TBI 与相对无毒的生物和药理学相结合 免疫抑制剂，包括 213Bi 标记的自然杀伤 (NK) 细胞抗体，均旨在 降低宿主 NK 和 T 细胞反应以及移植物的 T 细胞反应性。另一个是管理 移植后早期化疗不仅可以控制 GVHD，还可以促进移植。之后我们有 确定移植后化疗的最佳剂量和剂量后，我们将评估使用 供体细胞转染了耐药基因，这将允许使用更高剂量的移植后 化疗用于诱导供体嵌合和控制 GVHD。 GVHD 预防也将 包括用某些免疫抑制剂控制供体淋巴细胞的复制，例如 MMF 和 西罗莫司与 T 细胞共刺激阻滞剂联合使用。 我们的最终目标是为具有替代供体的患者开发同种异体 HCT 策略 短期和长期毒性最小，可成功应用于人类患者。